8926
A. K. Miller et al. / Tetrahedron 59 (2003) 8919–8930
(92.8%) of 12 as a colorless oil: Rf¼0.30 (silica, 15%
EtOAc in hexanes); IR (thin film) nmax¼3324 (br) 2963,
1.26 (t, J¼7.2 Hz, 3H), 1.05 (s, 3H), 0.96 (t, J¼7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 174.2, 144.1, 134.1, 129.3,
128.9, 60.5, 59.1, 43.1, 37.9, 33.7, 21.4, 14.6, 14.5, 14.5,
13.8, 12.5, 10.1; HRMS (EI): calcd for C17H26O2: 262.1932;
found: 262.1936; Anal. calcd for C17H26O2: C 77.82, H
9.99; found: C 78.16, H 10.20.
1
2933, 2872, 1447 cm21; H NMR (400 MHz, CDCl3): d
5.82 (s, 1H), 5.64 (s, 1H), 5.32 (t, J¼7.2 Hz, 1H), 4.26 (s,
2H), 2.10 (quint, J¼7.2 Hz, 2H), 1.86 (d, J¼1.6 Hz, 3H),
1.84 (s, 3H), 1.73 (s, 3H), 0.99 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 135.2, 133.4, 133.3, 133.0, 131.9,
131.6, 62.7, 22.8, 21.7, 19.0, 17.0, 14.3; HRMS (EI): calcd
for C12H20O: 180.1514; found: 180.1517.
5.2.8. (1S p,4S p,5R p,6S p) 1,3,6-Trimethyl-4-(1-methyl-
but-1-enyl)-bicyclo[3.1.0]hex-2-ene-6-carboxylic acid
methoxy-methyl-amide (15). To a slurry of 14 (120 mg,
0.457 mmol) and N,O-dimethylhydroxylamine hydro-
chloride (226 mg, 2.32 mmol) in 2.0 mL of THF was
added a solution of isopropyl magnesium chloride (2.1 mL,
4.2 mmol, 2.0 M in Et2O) at 2108C under a blanket of
argon. The reaction mixture was allowed to warm to 238C
and, after 1 h, was quenched with 20 mL of a 1:1 mixture
of saturated NH4Cl and H2O and diluted with 20 mL of
Et2O. The two layers were separated and the aqueous layer
was extracted with Et2O (2£20 mL). The combined organic
layers were washed with 20 mL of brine, dried (MgSO4),
filtered, and concentrated in vacuo. The product was puri-
fied by column chromatography (25% Et2O in hexanes) to
yield 80.0 mg (63.1%) of 15 as a colorless oil: Rf¼0.13
(silica, 25% Et2O in hexanes); IR (thin film) nmax¼2963,
5.2.6. 2,4,6,8-Tetramethyl-undeca-(E)-2,(Z)-4,(E)-6,(E)-
8-tetraenoic acid ethyl ester (13). To a mixture of
12 (1.39 g, 7.71 mmol), NMO (1.40 g, 12.0 mmol), and
˚
3.50 g of 4 A molecular sieves in 30 mL of CH2Cl2 was
added TPAP (84.0 mg, 0.239 mmol) at 08C under a blanket
of argon. Immediately after the addition, the reaction flask
was wrapped in aluminum foil and allowed to warm to
238C. After 4 h, the reaction mixture was filtered through a
thin pad of silica and washed with CH2Cl2 (3£30 mL). The
combined filtrate was concentrated in vacuo to give 995 mg
of crude aldehyde 54 as a yellow oil that was used in the
next step without further purification. To a mixture of LiCl
(338 mg, 7.97 mmol), DBU (0.90 mL, 6.02 mmol), and
triethyl phosphonopropionate (4.16 g, 17.5 mmol) in 25 mL
of CH3CN was added a solution of crude aldehyde (995 mg,
5.58 mmol) in 35 mL of CH3CN at 238C under a blanket of
argon. After 5 h, the mixture was concentrated in vacuo and
diluted with 200 mL of H2O and 100 mL of Et2O. The two
layers were separated and the aqueous layer was extracted
with Et2O (2£50 mL). The combined organic layers were
washed with 50 mL of brine, dried (MgSO4), filtered, and
concentrated in vacuo. The product was purified by column
chromatography (1–5% Et2O in hexanes) to afford 860 mg
(42.5% from 12) of 13 as a colorless oil: Rf¼0.45 (silica, 5%
Et2O in hexanes); IR (thin film) nmax¼2954, 2932, 2873,
1
2931, 2870, 1658 cm21; H NMR (500 MHz, CDCl3): d
5.25 (t, J¼7.5 Hz, 1H), 5.23 (s, 1H), 3.71 (s, 3H), 3.23 (s,
3H), 2.62 (s, 1H), 2.01 (quint, J¼7.5 Hz, 2H), 1.69 (s, 1H),
1.53 (s, 3H), 1.45 (s, 3H), 1.22 (s, 3H), 1.03 (s, 3H), 0.95 (t,
J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 210.0, 144.3,
134.1, 128.8, 128.0, 60.6, 58.8, 40.3, 34.9, 34.6, 34.3, 21.4,
16.2, 14.5, 13.8, 12.6, 11.0; HRMS (EI): calcd for C17H27NO2:
277.2041; found: 277.2044; Anal. calcd for C17H27NO2: C
73.61, H 9.81, N 5.05; found: C 73.72, H 9.98, N 4.90.
5.2.9. (1S p,4S p,5R p,6S p) 1-[1,3,6-Trimethyl-4-(1-methyl-
but-1-enyl)-bicyclo[3.1.0]hex-2-en-6-yl]-propan-1-one
(16). To a solution of 15 (16.9 mg, 0.061 mmol) in 0.8 mL
of THF was added a solution of ethyl magnesium bromide
(0.20 mL, 0.60 mmol, 3.0 M in Et2O) at 08C under a blanket
of argon. After 3 h, the reaction mixture was quenched with
2.0 mL of a 1:1 mixture of saturated NH4Cl and H2O and
diluted with 2.0 mL of Et2O. The two layers were separated
and the aqueous layer was extracted with Et2O (2£2 mL).
The combined organic layers were dried (MgSO4), filtered,
and concentrated in vacuo. The product was purified by
column chromatography (5% Et2O in hexanes) to yield
13.0 mg (86.6%) of 16 as a colorless oil: Rf¼0.71 (silica,
25% Et2O in hexanes); IR (thin film) nmax¼2963, 2932,
1
1709 cm21; H NMR (400 MHz, CDCl3): d 7.45 (s, 1H),
6.01 (s, 1H), 5.78 (s, 1H), 5.34 (t, J¼7.2 Hz, 1H), 4.20 (q,
J¼7.2 Hz, 2H), 2.10 (quint, J¼7.2 Hz, 2H), 1.95 (s, 3H),
1.89 (d, J¼1.2 Hz, 3H), 1.83 (s, 3H), 1.73 (s, 3H), 1.29 (t,
J¼7.2 Hz, 3H), 0.98 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 168.9, 140.6, 137.5, 136.4, 133.4,
132.3, 132.1, 131.1, 127.2, 60.7, 31.8, 24.2, 21.8, 18.4, 17.0,
14.4, 14.2; HRMS (EI): calcd for C17H26O2: 262.1932;
found: 262.1930.
5.2.7. (1S p,d4S p,5R p,6S p) 1,3,6-Trimethyl-4-(1-methyl-
but-1-enyl)-bicyclo[3.1.0]hex-2-ene-6-carboxylic acid
ethyl ester (14). To a solution of 13 (425 mg, 1.62 mmol)
in 16 mL of CH2Cl2 was added a solution of dimethyl-
aluminum chloride (0.35 mL, 0.35 mmol, 1.0 M in hexanes)
at 08C under a blanket of argon. The reaction mixture was
allowed to warm to 238C and was wrapped in aluminum
foil. After 8 h, the reaction mixture was quenched with
15 mL of H2O. The two layers were separated and the
aqueous layer was extracted with CH2Cl2 (2£15 mL). The
combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. The product was purified by column
chromatography (5% Et2O in hexanes) to afford 312 mg
(73.4%) of 14 as a colorless oil: Rf¼0.34 (silica, 5% Et2O
in hexanes); IR (thin film) nmax¼2961, 2930, 2872,
2872, 1689 cm21 1H NMR (400 MHz, CDCl3): d 5.25
;
(s, 1H), 5.23 (t, J¼7.2 Hz, 1H), 2.65 (dq, J¼17.6, 7.2 Hz,
1H), 2.55 (s, 1H), 2.49 (dq, J¼17.6, 7.2 Hz, 1H), 2.07 (s,
1H), 2.01 (quint, J¼7.2 Hz, 2H), 1.55 (s, 3H), 1.45 (s, 3H),
1.13 (s, 3H), 1.11 (s, 3H), 1.04 (t, J¼7.2 Hz, 3H), 0.94 (t, J¼
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 211.0, 144.8,
134.2, 129.2, 128.8, 59.1, 45.2, 40.6, 37.1, 34.6, 21.4, 14.5,
14.0, 13.9, 12.6, 10.6, 8.3; HRMS (EI): calcd for C17H26O:
246.1985; found: 246.1983.
5.2.10. (1S p,4S p,5R p,6S p) 2,4-Dimethyl-3,5-dioxo-5-
[1,3,6-trimethyl-4-(1-methyl-but-1-enyl)-bicyclo[3.1.0]-
hex-2-en-6-yl]-pentanoic acid methyl ester (18). To a
solution of 16 (75.0 mg, 0.304 mmol) in 5.0 mL of THF was
1
1717 cm21; H NMR (400 MHz, CDCl3): d 5.25 (m, 2H),
4.13 (q, J¼7.2 Hz, 2H), 2.60 (s, 1H), 2.02 (quint, J¼7.6 Hz,
2H), 1.92 (s, 1H), 1.53 (s, 3H), 1.47 (s, 3H), 1.30 (s, 3H),
added a solution of lithium bis(trimethylsilyl)amide